1. Technical Field
The present invention is related to delivering selected agents through native or cloned IgE or any part thereof capable of binding with specificity to high affinity IgE Fc receptors. More particularly, the present invention is related to a selective delivery system comprising an agent to be delivered being linked in some manner with IgE Fc and targeting such agent to mast cells or basophils which express specific high affinity IgE Fc receptors.
2. State of the Art
The concept of utilizing a specific binding moiety as a vehicle for targeted delivery of a chemotherapeutic agent or toxin is well established. Cancer investigators, for instance, have attempted to exploit monoclonal antibodies to which are linked toxins in the search for selective ablation of tumor cells. The components of such a system are an antibody, a toxic moiety, and an agent for chemically conjugating the antibody with the toxic moiety. Recent reviews summarize the various methods of conjugation and the results of experiments utilizing hybrid molecules, called immunotoxins (Ghose et al., 1983 Academic Press, N.Y. 93:280; Ghose et al., 1978 J. Natl. Cancer Inst. 61:657; Jansen et al., 1980 Immunol. Letters 2:97; Neville et al., 1982 Immun. Review 62:75; Jansen et al., 1982 Immun. Review 62:185).
Although the linking agents utilized for conjugation, the species and isotype of the polyclonal or monoclonal antibodies employed, and the toxins have all been varied, one aspect of the immunotoxin experimentation has generally remained constant in as much as the binding of the immunotoxin to the target cells was accomplished via the Fab' terminus of the antibody portion of the conjugate. The Fc region of an antibody has also been employed as a vehicle for target delivery of a toxin to macrophages (Refsnes et al., 1976 J. Exp. Med. 143:1464). However, the class of antibody employed in such test was IgG.
It should be recognized that there are several known classes of immunoglobulins (Ig), for example IgG, IgM, IgA and IgD. Of course, such classification makes it prima facie evident that each class of immunoglobulin is distinctly different in its structure and function.
A particular class of immunoglobulin, termed IgE, has come to be recognized as being involved in the mechanism responsible for allergic disorders. Like other immunoglobulins, the IgE molecule is comprised of Fab' and Fc portions. The portion designated as Fab' determines the specific material in the body or environment that the molecule will react with, while the Fc portion determines on which cell the molecule will bind.
A variety of cells synthesize and express membrane glycoproteins that can bind the Fc portion of immunoglobulins with variable specificity and affinity. Depending on the degree of specificity and affinity, such Fc receptors can mediate a variety of cellular functions. There are, therefore, at least three factors which determine the functional role of a Fc receptor: (1) the type of Fc involved, that is whether it is an IgG or an IgE Fc and the like; (2) the range of specificity and (3) the degree of binding affinity.
A particular type of Fc receptors is found primarily on mast cells and basophils, which have an extraordinary high affinity for IgE Fc. These receptors are critical for initiating IgE-mediated allergic reactions. The feasibility, role and efficacy of preparing an IgE Fc linked immunotoxin for killing mast cells, basophils or any other cell or tissue which expresses high affinity IgE Fc receptors, have not heretofore been known or determined. It is noted that the mast cell, an effector cell involved in allergic diseases, is widely distributed throughout the body and there is currently a lack of specific therapy for patients with either malignant systemic mastocytosis or severe benign systemic mastocytosis, disorders characterized by an increased proliferation of the mast cells.